The current invention proposes topical administration of therapeutically effective doses of certain sesquiterpene epoxides (trichothecenes), to inhibit virtually every pathway involved in causing psoriasis.
The most fundamental function a cell is protein synthesis (i.e. expression of its DNA). Proteins make up xcx9c60% of a dry cell""s mass by weight. In very broad and general terms, as cells mature and differentiate in the body, they reach an equilibrium in protein synthesis and protein degradation and settle down to perform their given function in this relative state of homeostasis. There are two notable exceptions that cause massive perturbations to this homeostasis: 1) when a cell is called upon to grow and divide and 2) when certain secretory cells are called upon to produce large amounts of proteins for secretion. Although the cell signaling signaling pathways, intracellular transduction pathways, and spectrum of protein(s) to be produced are quite different in growth versus secretion, normal growth and secretion events share one major similarity in their end result: massively accelerated protein synthesis. A cell that is called on to grow (cycling cell) has as much as 5 times the protein synthesis activity of a non cycling cell and needs between 2,000 and 5,000 different enzymes and structural proteins to grow and divide. Likewise, secretory cells such as those of the immune system become protein factories producing massive amounts of antibodies, mediators, growth factors, or other proteins when stimulated to do so.
There are also abnormal conditions such as cancer and viral infections that share the same property of hyperactive protein synthesis versus normal quiescent cells. Cancer is a growth and divide type event, and even though the signaling mechanism is different in that it is self-induced intracellularly by several genetic mutations, the end result is also hyperaccelerated protein synthesis characteristic of a cycling cell. Viruses invade a cell, parasitize the host cellular machinery, and convert the cell into a factory producing massive amounts of viral proteins, much like a secretory cell.
Inhibiting protein synthesis affects cells in a dose dependent manner and affects actively cycling cells differently than non cycling cells. At low doses, protein synthesis inhibitors (PSIs) stop actively cycling cells from cycling without killing them (hereinafter referred to as inhibitory or G zero inducing dose). Inhibitory doses also stop hyperaccelerated protein synthesis by secretory cells. At moderate doses PSIs exhibit toxicity to actively cycling cells (hereinafter referred to as the cytotoxic dose). At high doses, PSIs exhibit toxicity to all cells (hereinafter referred to as the toxic dose).
Psoriasis presents as elevated lesions that vary in size between one to several centimeters.
Psoriasis is one of the most common dermatologic diseases, affecting about 2 percent of the population to some degree. There are actually several types of psoriasis, with plaque psoriasis being the most common, but the underlying problem in all of them is overproduction of epidermal cells. Instead of adhering to the 21 to 28 day cycle of cell turnover, those afflicted with psoriasis race through the cycle in 3 or 4 days. The epidermis may grow to 5 to 10 times its normal thickness. The thickened epidermis, overgrowth of blood vessels, and infiltrate of neutrophils and lymphocytes account for the psoriatic lesions being raised and easily palpable. The lesions may range from a few to many at any given time.
The etiology of psoriasis is still poorly understood, however evidence has accumulated clearly indicating a role for T cells. Hordes of activated T cells are found in psoriatic skin and almost none in healthy skin. It has also been discovered that these activated T cells secrete interleukin-6, which has as one of its effects the ability to stimulate skin cell growth. The infiltration of activated white blood cells suggest that an immune response has been mustered against something.
There are various theories about what that xe2x80x9csomethingxe2x80x9d is. One suggests a genetic abnormality as studies have shown concordant disease in 73% of monozygotic twins compared with 20% of dizygotic twins. The absence of 100% concordance among monozygotic twins suggests environmental factors must play a role. Other theories suggests that psoriasis is an immune system overreaction against invading organisms, or toxins produced by those organisms (xe2x80x9csuperantigensxe2x80x9d), as it is known that latent psoriasis can be activated by various infections as well as certain drugs and injury to the skin. Bone marrow transplantation has resulted in clearance of the disease. In any event, psoriasis is currently considered to be an immunologic skin disorder.
Three basic treatment modalities are used under prior art: 1) topical agents, 2) phototherapy, and 3) systemic agents.
Topical Therapyxe2x80x94Outpatient topical therapy is the first-line approach. Several topical treatments are available, however no single ideal topical agent exists for plaque psoriasis. Topical treatments available are corticosteroids, coal tar, anthralin, calcipotriene, tazarotene.
Topical corticosteroids are considered the treatment of choice for the face, neck, skin folds, and genitalia for symptomatic relief. All topical steroids have anti-inflammatory, anti-pruritic, and vasoconstrictive effects. However their long term use is often accompanied by loss of effectiveness (tachyphylaxis). Systemic absorption is always a risk as it can suppress the pituitary-adrenal axis and induce cushingoid features.
Coal tar contains literally thousands of different substances and the exact mechanisms of action is unknown, though an antimitotic effect has been ascribed to these substances.
Anthralin is a synthetic derivative of a tree bark extract and in an antiproliferative agent that may upset oxidative metabolic processes, decreasing rate of epidermal cell proliferation. Although anthralin is considered one of the most effective agents available, it is not in widespread use because of high potential to cause irritation and staining.
Calcipotriene is a synthetic vitamin D-3 analog that regulates skin cell production however is not in widespread use because it is expensive and no more than 100 g/wk can be used because of the risk of irritation, hypercalcemia, and vitamin D toxicity.
Tazarotene is a retinoid derivative which very commonly causes irritation and as such is typically used in conjunction with a topical steroid. Retinoid derivatives alter the delayed hypersensitivity response and increase the number of Langerhans cells in the psoriatic lesion. Tazarotene is particularly useful for psoriasis involving the scalp. For plaque psoriasis, retinoids can be used in combination with ultraviolet phototherapy to minimize the dose of each.
Phototherapyxe2x80x94Phototherapy is generally used only in the presence of extensive, widespread disease. Resistance to topical treatments is another indication for phototherapy. There are two main forms of phototherapy; UVB and PUVA.
UVB or Ultraviolet B uses light in the 290-320 nm wavelengths and is usually combined with one or more topical treatments including; coal tar followed by UVB (Goeckerman regimen), tar bath followed by UVB followed by anthralin (Ingram method), or UVB combined with topical corticosteroids, calcipotriene, tazarotene, or simply bland emollients. A major drawback is the time commitment required and accessibility to UVB equipment. PUVAxe2x80x94uses the photosensitizing drug methoxsalen (8-methoxypsoralens) in conjunction with UVA light (wavelengths in the 320-400 nm range). PUVA interferes with DNA synthesis (methoxsalen binds covalently to pyrimidine bases in DNA), decreases cellular proliferation, and induces apoptosis of cutaneous lymphocytes leading to localized immunosuppression. Adverse effects include nausea, pruritus, burning, photo damage to the skin and increased risk of skin cancer.
Systemic Agentsxe2x80x94Systemic Treatment is initiated only after both topical and phototherapy have failed or for patients with very active psoriatic arthritis. The main agents available are the immunomodulators Methotrexate and Cyclosporine and the oral retinoid Acitretin.
Methotrexate is a folic acid antagonist that inhibits DNA synthesis in tissues with high rates of turnover, such as psoriatic plaques, and is immunosuppressive to mononuclear cells in the skin, blood, and lymphatics. Methotrexate has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems.
Cyclosporine inhibits production of interleukin-2, the cytokine responsible for inducing T-Cell proliferation. Skin lesions recur within days to weeks after treatment is stopped. Adverse effects include hypertension, impaired renal function, and theoretically increased risk of cancer.
Acitretin is a second generation oral retinoid. The use of oral retinoid monotherapy has shown limited efficacy for chronic stable plaque psoriasis.
Harvey Lui, MD, FRCPC sums up the prior art situation well in the eMedicine Journal (Volume 2, Number 8): xe2x80x9cNo single ideal topical agent exists for plaque psoriasis.xe2x80x9d Compositions and methods of present invention will change that. The present invention provides topical compositions that have the ability to internalize rapidly into psoriatic tissue and inhibit virtually every aspect of psoriasis.
Novelty Over Prior Art Treatments of Psoriasis: Present invention overcomes the inability of prior art to provide a single topical agent for treatment of plaque psoriasis. It will be shown how compositions of present invention can be used to downregulate or shut down virtually every aspect of psoriasis. By binding to ribosomes and downregulating protein synthesis, it will be shown how compositions of present invention can be used to simultaneously; 1) directly stop cell cycling in basal layer epidermal stem cells (by dismantling the cell cycle control system), 2) directly stop cell cycling in endothelial cells (preventing angiogenesis), 3) depress production of growth factors underlying both epidermal and endothelial hyperactive growth, 4) depress activation of lymphocytes in response to antigens , and 5) retard maturation of differentiated epidermal cells.
Novelty and Unobviousness Over Prior Art Use of Trichothecene: Present Invention also overcomes prior arts inability to use trichothecene in treatment of hyperaccelerated growth conditions. Anguidine, a simple trichothecene, was tested against cancer and abandoned after Phase II testing showed a low tumor response and considerable hematologic toxicity. Prior arts attempt to remedy this failure are embodied in U.S. Pat. Nos. 4,906,452 and 4,744,981 which propose conjugates of trichothecene with monoclonal antibodies to enhance delivery to the tumor and glycosylation of trichothecene to increase blood solubility. Present invention takes a novel and unobvious approach that is exactly opposite to prior art in several respects. First, present invention reverses direction of administration (i.e. administered from tissue side to blood versus prior arts direction of blood to tissue). Second, present invention embraces the non specific internalization properties to deliver the greatest doses to tissues it is applied to and depending on those tissues to retain the trichothecene, preventing it from reaching general circulation (versus prior arts targeted delivery by monoclonal antibodies). Third, present invention embraces the use of macrocyclic trichothecene (versus simple trichothecenes in prior art) because the macrocyclic ring enhances rapid non specific internalization further enhancing localization and preventing entry into the blood. Fourth, present invention embraces blood insolubility to prevent entry into the blood (versus prior art glycosylation). Last, present invention uses inhibitory (non toxic) doses (versus prior arts toxic doses) and works primarily by dismantling the cell cycle control system versus killing the cell.